PMID- 32323104 OWN - NLM STAT- MEDLINE DCOM- 20201014 LR - 20220816 IS - 1179-1918 (Electronic) IS - 1173-2563 (Print) IS - 1173-2563 (Linking) VI - 40 IP - 6 DP - 2020 Jun TI - Clinical Drug-Drug Interaction Studies to Evaluate the Effects of a P-Glycoprotein Inhibitor, CYP3A Inhibitors, and a CYP3A Inducer on the Pharmacokinetics of Naldemedine in Healthy Subjects. PG - 529-540 LID - 10.1007/s40261-020-00902-w [doi] AB - BACKGROUND: Naldemedine is a peripherally acting mu-opioid receptor antagonist that is indicated to treat opioid-induced constipation. OBJECTIVES: To assess the potential for drug-drug interactions between a single oral dose of naldemedine and the oral P-glycoprotein inhibitor cyclosporine, cytochrome P450 (CYP) 3A inhibitors itraconazole and fluconazole, and CYP3A inducer rifampin. METHODS: Three Phase 1, open-label studies were conducted in healthy subjects. In the P-glycoprotein inhibitor study, subjects received naldemedine 0.4 mg alone or coadministered with cyclosporine 600 mg. In the CYP3A inhibitors study, subjects in separate cohorts received naldemedine 0.2 mg alone or with itraconazole or fluconazole. In the CYP3A inducer study, subjects received naldemedine 0.2 mg alone or with rifampin 600 mg. Geometric mean ratios and 90 % confidence intervals were used to evaluate the effects of coadministered drugs on naldemedine maximum plasma concentration (C(max)) and the area under the concentration-time curve (AUC). Safety assessments included occurrence of adverse events (AEs), laboratory parameters, vital signs, and electrocardiography results. RESULTS: A total of 56 subjects were enrolled (n = 14 in each cohort). Cyclosporine increased naldemedine AUC(0-inf) 1.78-fold and C(max) 1.45-fold. Itraconazole and fluconazole increased naldemedine AUC(0-inf) 2.91-fold and 1.90-fold, and C(max) 1.12-fold and 1.38-fold, respectively. Rifampin decreased naldemedine AUC(0-inf) by 83% and C(max) by 38%. Across studies, AEs were generally mild. Laboratory, vital sign, or electrocardiogram assessments produced no clinically significant findings. CONCLUSIONS: Coadministration of naldemedine with a P-glycoprotein inhibitor or a strong/moderate CYP3A inhibitor increases naldemedine exposure; coadministration with a strong CYP3A inducer decreases its exposure. Coadministration of naldemedine with cyclosporine, itraconazole, fluconazole, or rifampin was generally safe and well tolerated. FAU - Fukumura, Kazuya AU - Fukumura K AUID- ORCID: 0000-0001-9434-1938 AD - Clinical Pharmacology and Pharmacokinetics, Project Management Department, Shionogi & Co, Ltd, 1-1-4 Shibata, Kita-ku, Osaka, 530-0012, Japan. kazuya.fukumura@shionogi.co.jp. FAU - Kawaguchi, Nao AU - Kawaguchi N AUID- ORCID: 0000-0002-9382-2382 AD - Clinical Pharmacology and Pharmacokinetics, Project Management Department, Shionogi & Co, Ltd, 1-1-4 Shibata, Kita-ku, Osaka, 530-0012, Japan. FAU - Ishibashi, Toru AU - Ishibashi T AUID- ORCID: 0000-0003-3383-9980 AD - Clinical Pharmacology and Pharmacokinetics, Project Management Department, Shionogi & Co, Ltd, 1-1-4 Shibata, Kita-ku, Osaka, 530-0012, Japan. FAU - Kubota, Ryuji AU - Kubota R AUID- ORCID: 0000-0003-1979-4472 AD - Clinical Pharmacology and Pharmacokinetics, Project Management Department, Shionogi & Co, Ltd, 1-1-4 Shibata, Kita-ku, Osaka, 530-0012, Japan. FAU - Tada, Yukio AU - Tada Y AUID- ORCID: 0000-0003-4802-9307 AD - Biostatistics Center, Shionogi & Co, Ltd, Osaka, Japan. FAU - Ogura, Eriko AU - Ogura E AUID- ORCID: 0000-0002-9671-8572 AD - Global Development Division, Shionogi & Co, Ltd, Tokyo, Japan. LA - eng PT - Journal Article PL - New Zealand TA - Clin Drug Investig JT - Clinical drug investigation JID - 9504817 RN - 0 (Analgesics, Opioid) RN - 0 (Cytochrome P-450 CYP3A Inducers) RN - 0 (Cytochrome P-450 CYP3A Inhibitors) RN - 0 (Receptors, Opioid, mu) RN - 03KSI6WLXH (naldemedine) RN - 5S6W795CQM (Naltrexone) SB - IM MH - Adolescent MH - Adult MH - Analgesics, Opioid/adverse effects MH - Area Under Curve MH - Clinical Trials, Phase I as Topic MH - Constipation/chemically induced/drug therapy MH - Cytochrome P-450 CYP3A Inducers/*pharmacokinetics MH - Cytochrome P-450 CYP3A Inhibitors/*pharmacology MH - Female MH - Healthy Volunteers MH - Humans MH - Male MH - Middle Aged MH - Naltrexone/*analogs & derivatives/pharmacokinetics MH - Receptors, Opioid, mu/antagonists & inhibitors MH - Young Adult PMC - PMC7242238 OAB - Naldemedine is a targeted medication approved in the USA, Europe, and Japan for the treatment of opioid-induced constipation. Symptoms of constipation may include passing fewer stools than usual, having lumpy or hard stools, and/or straining to have bowel movements. In some cases, these symptoms are side effects of regular opioid use, which is often medically necessary for the management of moderate-to-severe pain. For naldemedine to be prescribed safely, doctors must know what other medications a patient is taking and how these medications may affect one another. This is commonly known as drug-drug interactions. Some drug-drug interactions may decrease how well a medication works, while other drug-drug interactions may increase the side effects experienced by a patient. In this paper, researchers report the results of three Phase 1 studies in healthy subjects examining how naldemedine interacts with other drugs. The drugs chosen for investigation are commonly evaluated in DDI studies and may affect the transport or metabolic pathway of naldemedine, including the P-glycoprotein inhibitor cyclosporine, the CYP3A inhibitors itraconazole and fluconazole, and the CYP3A inducer rifampin. These studies demonstrate that co-administration of naldemedine with each of these drugs impacted the pharmacokinetics of naldemedine. Cyclosporine, itraconazole, or fluconazole all increased naldemedine exposure, while rifampin decreased naldemedine exposure. For all drug combinations, observed side effects were generally mild and well tolerated. Additional testing, including vital signs and heart monitoring, did not reveal any other safety concerns. In conclusion, these findings support the cautious use of naldemedine in combination with cyclosporine, itraconazole or fluconazole. Concomitant use with rifampin should be avoided. OABL- eng COIS- Kazuya Fukumura, Nao Kawaguchi, Toru Ishibashi, Ryuji Kubota, Yukio Tada, and Eriko Ogura are employees of Shionogi & Co, Ltd. EDAT- 2020/04/24 06:00 MHDA- 2020/10/21 06:00 PMCR- 2020/04/22 CRDT- 2020/04/24 06:00 PHST- 2020/04/24 06:00 [pubmed] PHST- 2020/10/21 06:00 [medline] PHST- 2020/04/24 06:00 [entrez] PHST- 2020/04/22 00:00 [pmc-release] AID - 10.1007/s40261-020-00902-w [pii] AID - 902 [pii] AID - 10.1007/s40261-020-00902-w [doi] PST - ppublish SO - Clin Drug Investig. 2020 Jun;40(6):529-540. doi: 10.1007/s40261-020-00902-w.